The concept of targeting cancer therapeutics towards specific mutations or abnormalities in tumor cells which are not found in normal tissues has the potential advantages of high selectivity for the tumor and correspondingly low secondary toxicities. At least 93% of pancreatic cancers have the identical activating mutation at position 12 in the Ki-Ras gene. We previously discovered that over-activity of p21Ras signaling causes tumor cell apoptosis when PKCd activity is suppressed. In contrast, PKCd activity is not required for the survival and growth of normal cells (with wild-type Ras). This absolute dependency of Ras-mutant tumor cells on PKCd activity can therefore be exploited as a targeted cancer therapeutic. (This novel molecular approach, which spares normal cells, targets the dependency of tumor cells containing a mutated oncogenic protein on a second, non-oncogenic protein required for survival of the tumor, sometimes termed non-oncogene addiction). In our work to date, we have characterized this synthetic lethality approach molecularly, demonstrated its selectivity in vitro and in vivo, and identified two lead compounds for efficiently inducing cell death in tumors containing activated Ras. In this proposal, we will refine and explore our lead PKCd inhibitor by generating specific analogs, and then use in vitro and in vivo studies to select the optimal candidate drug for inducing synthetic lethality in pancreatic carcinoma. In future work, we will then move the selected compound forward, into formal preclinical studies. We have an excellent track record of developing novel therapeutics from discovery through phase II trials from within an academic setting. In addition, we will continue to employ, and continuously refine, our molecular strategy (a highly-predictive pharmacophore model) in the search for even more active and more specific inducers of Ras-targeted synthetic lethality. Furthermore, our targeted approach appears to have substantial activity against pancreatic cancer stem cells, which are generally refractory to conventional chemotherapy. Our Aims are: i.) Targeted chemical modifications of current lead PKCd inhibitor; ii.) Test these new PKCd inhibitors in human pancreatic cancer cells for induction of apoptosis; iii.) Validate this Ras-targeted approach in in vivo models of human pancreatic carcinoma. This novel therapeutic modality, selectively targeting pancreatic carcinomas, would make a significant impact on the way pancreatic carcinoma is treated.